Abstract/Summary: Few studies have evaluated the possible risk for adult leukemia associated with a family cancer history. Such a link can provide the impetus for further studies of specific genes and modes of inheritance. Since family history of cancer is a composite variable representing shared genes as well as exposures, family history may identify individuals with increased susceptibility due to increased likelihood of having one or more of several gene polymorphisms that are involved in cancer etiology. We used data from a completed study of environmental factors risk factors for leukemia in adults to assess the leukemia risk associated with a family cancer history and to explore possible gene-environment interactions. Cases and controls provided information on cancer incidence and mortality in enumerated first and second-degree relatives and on their own exposure to known and suspected risk factors for leukemia. Relatives reported to have died since the advent of the National Death Index (NDI) were linked with that database in an attempt to validate cause of death. For those reported to have died prior to the NDI or for whom NDI matches were not found, death certificates were requested from individual states. Analyses focused on history of any cancer in any first degree relative, history of specific cancers in any first degree relative, and history of any or specific cancers in specific first degree relatives (e.g. in siblings) and on the relationship of family cancer history with risk for specific leukemia subtypes. We submitted requests for death certificates for 1058 of 2485 deceased relatives in the study. ?Match rates? were under 50% for NDI searches (done without Social Security number) and over 70% for state vital record searches. 83% of reported cancers in relatives could be confirmed with a death certificate; Negative cancer histories were confirmed 95% of the time. Site-specific matches were generally lower. A family history of any cancer, hematopoietic cancer, leukemia, and breast cancer was associated with increased leukemia risk when analysis was limited to respondents whose data collection was through a proxy because of illness or death. A family history of breast cancer in a sibling was associated with leukemia risk, regardless of interview type. . We also found that persons with both a family history of breast cancer and one of several environmental risk factors (smoking, solvents, radiation) are at greater risk for leukemia than those with either one of these risk factors. In fact, for each of the exposures examined, increased risk for leukemia was observed only among persons with a family history of breast cancer. Family history of breast cancer may be a marker of susceptibility to a range of leukemia risk factors whose effects are generally weak or non-existent when considered alone.